The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategies involve the use of positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on brain activity using cerebral metabolic rates for glucose using [F-18]fluorodeoxyglucose, regional cerebral blood flow using [O-15]-water and functional magnetic resonance imaging (fMRI) using the BOLD method. All of these methodologies provide indirect indices of neuronal activity. In a PET blood flow study using 20 control subjects, we observed activation of the anterior cingulate, orbital frontal, dorsolateral prefrontal and inferior parietal cortices, insula and thalamus predominantly on the right side during decision-making (Iowa gambling task). This task also activated the cerebellum predominantly on the left side. Studies of individuals with histories of cocaine abuse, who were abstinent for 25 days, compared to a matched control group demonstrated differential effects on blood flow while the participants performed tasks of inhibitory processing (Stroop Color Word Interference task) and decision-making (Iowa gambling task). While performing the Stroop task, abusers displacyed activation in the left anterior cingulate cortex and right dorsolateral prefrontal cortex than control subjects. Whereas, compared to control subjects performing the Gambling task, cocaine abusers had greater activation in the right orbital frontal cortex and less activation in the dorsolateral prefrontal cortex bilaterally. Grams per week of cocaine used prior to the 25-days abstinence period correlated negatively with normalized blood flow in the predicted regions of interest for both tasks. In another PET blood flow study, preliminary results indicate reduced normalized blood flow in the orbitofrontal cortex, hippocampus, and amygdala in abstinent drug abusers relative to control subjects during performance of executive and emotional function tasks. In addition, physiological responses measured by skin conductance and heart rate were altered in substance abusers during tests of executive function. These results suggest that both cognitive impairment and reduced blood flow characterize drug abusers, and that these differences persist after a minimum of three months of abstinence. PET studies of glucose utilization during a continuous performance task in individuals with a history of opiate abuse showed that detoxified opiate abusers previously on methadone maintenance therapy had lower normalized glucose metabolism in the left midcingulate gyrus, the left superior frontal cortex and the insula, bilaterally compared to individuals who had no history of drug abuse. Methadone maintained opiate abusers also had lower metabolism in the left insula, but higher metabolism in the left inferior parietal cortex. These results suggest that opiate addiction leads to abnormalities in neural circuitry subserving negative affective states and the methadone maintenance alleviates these abnormalities. Voxel-based morphometry (VBM) is being used to detect tissue density differences in gray matter and white matter on the acquired structural MR images. To date, we have used VBM to evaluate tissue density differences in a group of 14 cocaine abusers and a group of 11 non-users. Based on a priori hypotheses derived from O-15 PET imaging of these participants, we looked at tissue density differences restricted to the frontal cortex. In 10 of 13 frontal regions, the cocaine abuse group had lower gray matter density than the non-users group. These regions included the cingulate gyrus and medial and lateral aspects of the orbitofrontal cortex. These results extend our findings of altered cerebral blood flow to include abnormalities in gray matter tissue in the same frontal regions. Matochik JA, London ED, Eldreth DA, Cadet J-L, Bolla KI. Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study. NeuroImage 2003; 19:1095-1102. After installation of a Siemens 3 testa MRI, new MRI staff were hired including 3 Staff Clinicians, a senior MRI physicist and 3 MRI research associates, a signal processing physicist, an MRI operator, 2 IRTA postdoctoral fellows and 2 research technologists. Following the typical startup/acceptance period for the magnet, research involving several new, IRB-approved human protocols have begun. These protocols involve the investigation of various drugs of abuse using functional MRI (fMRI) and the BOLD (Blood Oxygen Level Dependant) technique. This technique uses changes in blood oxygenation, mostly due to changes in blood flow, as an indirect marker of neuronal activity. The new protocols include looking at the effects of marijuana and nicotine withdrawal on cognitive and affective processes in the brain, examining how acute nicotine administration affects attentional and cognitive process, and investigating the pharmacokinetic and pharacodynamic sites of action of nicotine under a variety of administration conditions. In addition to these protocols, the MRI Physics Unit has started work on the development and optimization of MRI pulse sequences to enhance our scanners abilities to acquire data. Especially relevant are pulse sequences tailored to improve signal loss from orbitofrontal and medial temporal regions of the brain, areas implicated in drug abuse. We are also working on improved Arterial Spin Labeling pulse sequences, for absolute quantification of blood flow, and Diffusion Tensor Imaging, to investigate changes in fiber tracking associated with drugs of abuse.